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Major Modifications and Additions to HMC IRB Manual 2/01/2010
Page # Modification/Addition Justification
14 IRB member with a COI is not counted toward quorum FDA and OHRP
guidance
15 Policy and Procedure manual fully reviewed every 2
years
Reflects current
practice. Interim
changes reviewed and
approved by IRB.
18 Administrative fee increased (from $1500 to $2000) Reflects current
practice
25, 28 FDA contacts for reporting
Facilitate reporting
33 Faculty member who is investigator must accompany
resident/student when the resident/student is presenting
to IRB
Reflects current
practice.
34 Telephone conference for IRB meeting Allowed in
extraordinary
circumstances. OHRP
guidance 3/28/2000
44-47 Continuing Review Chapter updated Per OHRP guidance
10/20/09
53-55 Adverse Event and Unanticipated Problems Chapter
updated
Per OHRP (12/17/09)
and FDA (4/2007)
guidance
56-58 Protocol Deviation Chapter added Reflects current
practice.
59-60 Quality Improvement Audit Chapter added Reflects current
practice.
64
Consent Document Handling Clarified Reflects current
practice.
68 Definition of Children updated
Pennsylvania Law –
35 P.S. 10101 (2004)
86-88 IND/IDE guidance added Facilitate assistance to
investigator
89-93 HUD Procedure added Reflects current
practice.
HAMOT MEDICAL CENTER
INSTITUTIONAL REVIEW BOARD
POLICY AND PROCEDURE MANUAL FOR THE
PROTECTION OF HUMAN RESEARCH
SUBJECTS
2010
These policies and procedures have been developed in conjunction with
FDA and HHS Guidelines and Regulations for Institutional Review Boards
Regarding Human Research Subjects.
February 01, 2010
TABLE OF CONTENTS
CHAPTER PAGE I. INSTITUTIONAL REVIEW BOARD
A. Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ……………. 1
B. Governing Principles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . …………… 2
C. Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ……………..4
D. Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... …………….. 6
1. Appointment . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ………… 6
2. Nominating Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . ………… 7
3. Designation and Election of Officers . . . . . . . . . . . . . . . . . . ………. 7
4. Length of Service/Termination . . . . . . . . . . . . . . . . . . . . . . ……….. .7
and Resignation of Membership
5. Removal . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . .…………….. 7
6. Attendance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ……………. 7
7. Vacancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ………….. 7
8. Compensation . .. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . …………… 8
9. Indemnification . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . ………………8
10. Conflict of Interest . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . ………….. 8
11. Confidentiality……………………………………………………... 10
E. IRB Members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ……………….10
F. Duties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ………………….10
G. Meetings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...…. ……………….. 13
1. Roberts Rules of Order . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Date/Time/Place . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2. Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 13
3. Minutes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ‘. . . 14
4. Order of Business. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5. Quorum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
H. Changes to Policies and Procedures . . . .. . . . . . . . . . . . . . . . . . . …………. 15
I. Records . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . ……………… 15
J. Authority of the IRB . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . …………….. 17
K. Education of New IRB Chairperson and Members . . . . . . . . . . . . . ……… 18
L. Education of Investigators and Coordinators .. . . . . . . . . . . . . . . . ………… 18
M. Resources of the IRB. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . …………….. 18
N. IRB Administrative Fee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . …………… 18
II. SUSPENSION AND TERMINATION OF A CLINICAL INVESTIGATION . . . .. .20
III. APPEAL PROCEDURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ……………… 31
IV. QUORUM, EXPEDITED, AND EXEMPT REVIEW . . . . . . . . . . . . . . . . ……….. 32
CHAPTER (cont'd) PAGE
V. MONITORING STUDIES: CONTINUING AND FINAL REVIEWS. . . ….……. 44
VI. STUDY PERSONNEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. …………………… 48
VII. ADVERSE EVENTS AND UNANTICIPATED PROBLEMS . …………………. 53
VIII. PROTOCOL DEVIATIONS………………………………………………………..56
IX. QUALITY IMPROVEMENT AUDIT………………………………………………59
X. INFORMED CONSENT . . . . . . . . . . .. . . . . . . . . . . . . . . . ……………….…….. 61
XI. INFORMED CONSENT OF SPECIAL RISK GROUPS . . .. . . . . . . ..………….. 68
XII. TEST ARTICLE . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . …………. ……………. 80
XIII. EMERGENCY (ONE-TIME) USE OF A TEST ARTICLE . . . . . . . . . . . . . ……. 93
XIV. EMERGENCY (PLANNED) RESEARCH. . . . . . . . . . . . . . . . . . . . . …………… 98
XV. USE OF TEST ARTICLE FROM SECOND INSTITUTION . . . . . . . . . . . . . ………….. 102
XVI. UNLABELED USE OF APPROVED DRUGS, BIOLOGICS, AND DEVICES . . . …….103
XVII. RECRUITING MATERIALS . . . . . . . . . . . . . . . . . . . . . . . . . . .…………………………. 105
XVIII. HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT……………..108
XIX. TISSUE REPOSITORIES AND RESEARCH DATABASES……………………. 116
APPENDIX
A. Glossary
B. By-laws of Hamot Health Foundation
C. Hamot Health Foundation Policies:
1. "Standards of Conduct in Research, “Conflict of Interest in Research”; “Research
Misconduct or Conflict of Interest Reporting”; “Research Misconduct/Conflict of
Interest Inquiry and Investigation, Initiating and Managing A"
2. "Research Approval, Registration, Grants and Awards"
3. "Hamot Medical Center, Medical Staff Rules and Regulations"
4. "Investigational Drugs", "Accountability Record", "Notification
of Emergency (One-Time) Use of an Investigational Test
Article Form"
5. "Bayside Pharmacy Policy and Procedure -
Investigational Drugs"
D. Forms
1. Guide to Research Protocol Development
2. Documentation of Research Approval
3. Institutional Review Board Application
4. Continuing/Final Review Form
5. Medical Records Release of Statistical Information
6. Consent for Non-IRB Research
E. Letters
1. Approval (Investigator Responsibilities)
2. Exemption from Approval
3. Modification
4. Expedited Review
5. Continuing Review Notification
6. Continuing Review Approval
7. Final Review
8. Miscellaneous
F. Humanitarian Use Devices
G. Risk Assessment
H. Miscellaneous
1. Study Summary Chart
2. IRB Roster
3. Educational Packet – New IRB members
4. Educational Program - Researchers
I. Forms for reporting SAEs and UPs
1. Serious Adverse Event form
2. Unanticipated Problem Form
J. Protocol Deviation Form
K. Quality Improvement Audit
L. HUD Investigator Release Form
M. FDA Telephone numbers
N. HIPAA forms
1. Business Associate Agreement
2. Disclosure Flag Form
PREFACE
This document is a complete revision of the Hamot Medical Center Institutional Review
Board (IRB) Manual and incorporates the changes that have occurred in federal regulations since
1991. The IRB shall follow these written policies and procedures for the Protection of Human
Research Subjects that have been approved by the IRB and by the Board of Trustees of the Hamot
Medical Center.
The genesis of current federal regulatory authority regarding clinical investigation of drugs,
biologicals, and devices (collectively called test articles) involving human subjects, lies principally
in the federal Food, Drug, and Cosmetic Act, particularly the Drug Amendments of 1962, the
Medical Device Amendments of 1976, and the 1995 Office of Health Affairs Information Sheets for
IRBs and Clinical Investigators. In addition, clinical investigations are also subject to the regulations
promulgated under the federal Public Health Services Act.
The following policies and procedures address IRB functions regarding those clinical
investigations regulated by the Food and Drug Administration (FDA) and for research of human
subjects regulated by Health and Human Services (HHS). A clinical investigation or human subject
research may be covered simultaneously by both FDA and HHS regulations. Generally, HHS
regulations apply only to human subject research conducted by HHS or funded in whole or in part by
an HHS grant, contract, cooperative agreement, or fellowship. Any human subject research not
directly related is not subject to HHS regulations. However, the Hamot Medical Center (HMC) IRB
requires all protocols to comply with the regulations of both FDA and HHS.
1
CHAPTER I
INSTITUTIONAL REVIEW BOARD
The Surgeon General of the United States issued a formal policy statement in 1966 protecting
human subjects in research sponsored by the Public Health Service. In response to that
statement, HMC formed an IRB for the Protection of Human Research Subjects (Glossary:
Appendix A).
A. Purpose
The purpose of the IRB is to protect the rights and welfare of individuals who serve as
subjects of research conducted by HMC physicians, staff, students, and others as
approved by the Chairperson and to ensure institutional compliance with the Code of
Federal Regulations related to research (45 CFR 46; 21 CFR 50, 54, 56, 312, 812).
To meet these obligations, the IRB:
maintains operating policies and procedures (as contained in this document)
demanding the highest professional standards related to human subjects, and
systematically reviews all research projects involving human subjects to ensure
that appropriate standards are met and research procedures do not infringe
upon the safety, health, welfare, or life of those subjects.
2
B. Governing Principles
The basic tenets underlying the IRB policies and procedures are respect for
individuals and their rights and welfare. Statements supporting the ethical principles
and standards adopted by the IRB can be found in the following major documents and
policies, which are on file in the IRB office:
Documents
The Declaration of Geneva
The Nuremburg Code
The Helsinki Declaration
The Belmont Report
The IRB policies and procedures are based on the following general ethical principles:
1. The rights and welfare of all subjects must be adequately protected. This
principle applies to the need for safeguarding the physical and psychological
well being of a subject, as well as preserving the subject's rights of privacy and
choice.
2. Risks must be minimized by using procedures that are consistent with sound
research design that do not expose subjects to unnecessary risk. When
appropriate, investigators should use standard procedures or those already
being used on the patient for diagnosis or treatment.
3. Risks must be reasonable in relation to anticipated benefits to subjects or to
importance of the knowledge that may be gained. The IRB reviews all
research for scientific and clinical merit with respect to the risk or benefit to
human subjects, including the anticipated benefits from the knowledge that
may be expected to result.
4. Recruitment and selection of subjects must be equitable within the confines of
the purposes and design of the study; subjects must not be arbitrarily excluded
on the basis of age, gender, race, national origin, religion, creed, education, or
socioeconomic status.
3
5. Informed consent, when required, must be obtained from each subject or the
subject's authorized representative by the physician or an authorized
representative.
a. The informed consent process must be documented by a written consent
form containing the "basic elements" and additional elements, as
appropriate, a copy of which must be given to the subject at the time the
subject's signature is obtained.
b. To the fullest extent possible, the subject's consent must be based upon
his/her understanding of the research, the risks, possible discomfort,
benefits, and any alternative procedures that are available.
c. The informed consent document must provide for the opportunity of the
subject to refuse participation or to discontinue participation at any time
without prejudice or loss of adequate medical care or treatment.
6. Provisions must be made to monitor data to ensure the safety of subjects.
7. Adequate provisions must be made to protect the privacy of subjects and the
confidentiality of data. Also, the IRB must be satisfied that questionnaires and
protocols involving sensitive issues are carefully designed to avoid gathering
more personal data than is necessary to do the research. (An example is
information that could, if it became known outside the research setting, place
the subject at various physical or social risks.)
8. Additional safeguards must be included in the study to protect the rights and
welfare of subjects who are likely to be vulnerable to coercion or undue
influence or who belong to potentially vulnerable populations (eg, fetuses,
children, prisoners, mentally deficient).
In addition, several professional organizations and societies have formulated their
own guidelines for research involving human subjects. Such guidelines can augment,
but not diminish the protection and requirements outlined herein.
4
FDA regulations require IRB review and approval of regulated clinical investigations,
whether or not the study involves hospitalized subjects. Hamot Medical Center IRB
requires that all HMC physicians and investigators receive approval from the HMC
IRB if the study involves hospitalized subjects. HMC IRB approval is not required
when an investigator's study has received prior approval by another IRB, involves
ambulatory patients, and takes place in the investigator's office, except when the
investigation is performed in a Hamot owned ambulatory site or practice. Submission
of a proposal to HMC IRB by an investigator who is not employed or privileged by
Hamot requires prior consent of the HMC IRB Chairperson and Administrator. If
consent for review is granted, the investigator agrees to abide by all HMC policies and
procedures including, but not limited, to those described in Appendices B & C1-5.
(Note: The investigator may also obtain review from another community hospital,
university, medical school, an independent IRB, or a local or state government health
agency or other organizations. However, when HMC patients are study subjects, the
study must be reviewed and approved by the Hamot IRB, as appropriate.)
C. Assurance
The Hamot Medical Center will comply with the policy for the protection of human
subjects participating in activities supported directly or indirectly by grants or
contracts from the Department of Health & Human Services (HHS). In fulfillment of
5
its assurance, this institution will:
1. establish and maintain a committee, called the Institutional Review Board
(IRB), competent to review projects and activities that involve human subjects.
The committee will be assigned responsibility to determine for each activity as
planned and conducted that:
the rights and welfare of subjects are adequately protected,
the risks to subjects are outweighed by potential benefits, and
the informed consent of subjects will be obtained by adequate and
appropriate methods;
2. provide for committee reviews to be conducted with objectivity and in a
manner to ensure the exercise of independent judgement of the members;
3. encourage continuing constructive communication between the IRB and the
project directors as a means of safeguarding the rights and welfare of subjects;
4. maintain appropriate and informative records for all IRB reviews of
applications and active projects, documentation of informed consent, and other
documentation that may pertain to the selection, participation, and protection
of subjects, and for reviews of circumstances that adversely affect the rights or
welfare of individual subjects;
5. periodically reassure itself, through appropriate administrative overview, that
the practices and procedures designed for the protection of the rights and
welfare of subjects are being effectively applied and are consistent with its
assurance as accepted by HHS;
6
6. bear primary responsibility for prevention and detection of research
misconduct and for the inquiry, investigation, and adjudication of research
misconduct alleged to have occurred in association with HMC.
D. Composition:
The IRB shall be sufficiently qualified through the experience and the expertise of its
members and the diversity of their backgrounds, including racial and cultural, and
sensitivity to such issues as community attitudes, to promote respect for its advice and
counsel in safeguarding the rights and welfare of human subjects. Every
nondiscriminatory effort will be made to ensure that the IRB does not consist entirely
of men or entirely of women; however, selection should not be made solely on the
basis of gender. Also, the IRB may not consist entirely of members of one profession.
The IRB must be able to ascertain the acceptability of proposed research in terms of
HMC commitments and regulations, applicable laws, and standards of professional
conduct and practice. The IRB shall, therefore, include persons knowledgeable in
these areas (Appendix H: Composition, Roster).
1. Appointment:
The IRB is a formal, standing committee of a minimum of eleven men and
women appointed by and responsible to the Hamot Health Foundation
Board of Trustees. Members are appointed annually (Appendix B).
2. Nominating Committee:
The Nominating Committee shall consist of the Board of Trustees who
accept recommendations from the IRB Chairperson, Vice Chairperson,
Administrator, and the Senior Vice President of Medical Affairs.
7
3. Designation and Election of Officers:
Officers of the IRB shall include the Chairperson and the Administrator.
One Vice Chairperson may be elected. Officers and members are elected at
the Annual Meeting of the Board of Trustees, to serve until the next annual
meeting or until successors have been elected.
4. Length of Service/Termination and Resignation of Membership:
No limit exists on the length of service of the Chairperson or members.
They, however, may resign at any time by giving notice of his/her
resignation in writing to the Chairperson or Administrator, as appropriate.
Such resignation shall be effective upon receipt by the Chairperson or
Administrator unless otherwise stipulated.
5. Removal
The IRB, by a two-thirds majority vote of the whole number of members,
may terminate the membership of any member of the IRB, subject to Board
of Trustee approval. Notice of the IRB meeting at which such action takes
place shall be given in writing to the member at least ten days before the
date of the meeting and sent by first class mail to his/her last known
address. The member shall have the right to speak on his/her own behalf
before the IRB at that meeting before any final vote is taken on his
removal. Failure of the member to attend that meeting shall be deemed to
be a waiver of that right.
6. Attendance:
Members who fail to attend four consecutive meetings of the IRB shall,
unless such absences are specifically excused by the IRB, be considered as
having resigned as a member of the IRB.
7. Vacancies:
Vacancies occurring on the IRB at a time other than at the annual meeting
of the Board of Trustees, including those by resignation or removal, shall
be filled by the affirmative vote of a majority of the remaining IRB
members, even if these remaining constitute less than a quorum of the IRB,
subject to Board of Trustees approval at their regular monthly meeting.
8
8. Compensation:
Members of the IRB shall receive no compensation for any services
rendered in those capacities. However, nothing contained herein shall be
construed to preclude any member from receiving compensation from the
Corporation for other services actually rendered or for expenses incurred
for serving the Corporation or in any other capacity.
9. Indemnification:
All employees and agents of the corporation are indemnified by the
corporation as described in Article VIII of the Institutional Bylaws
(Appendix B).
10. Conflict of Interest:
Institution. Any financial relationship existing between Hamot and a
commercial sponsor will be reported to the IRB Chairperson by the
individual providing administrative approval. The IRB Chairperson will,
in turn, report the details of this relationship to the IRB at the time of
initial review. The IRB will evaluate the nature of the financial
relationship using standards set forth in the policies: 1) Conflict of Interest
in Research, 2) Research Misconduct or Conflict of Interest, Reporting; 3)
Research Misconduct/Conflict of Interest Inquiry and Investigation,
Initiating and Managing a. If a conflict exists, the IRB will decide, in
conjunction with the Institution, how it can best be managed. If the
conflict cannot be adequately managed, the research cannot be approved.
IRB members. Each member will complete a Conflict of Interest
Declaration Form annually. This information will be summarized and
provided to the Chairperson. IRB members will receive a written reminder
in each meeting packet that they are required to abstain from voting on any
research protocol in which they have a conflict of interest. The IRB
member must remove him/herself from the room during the vote. (This
member may, however, be present for discussion to act as consultant.)
9
Investigators. Investigators who are members of the Board of Trustees
may not be involved in nominating members for the IRB.
If the investigator reports a possible conflict of interest on the IRB
Request for Approval form, the Administrator will obtain more specific
information from the investigator regarding the potential COI and report
this information to the IRB at initial study presentation. The IRB will
evaluate the type and extent of the potential conflict of interest using
standards set forth in the policies: 1) Conflict of Interest in Research, 2)
Research Misconduct or Conflict of Interest, Reporting; 3) Research
Misconduct/Conflict of Interest Inquiry and Investigation, Initiating and
Managing a.
After discussion, the IRB may find:
1) no significant conflict of interest exists;
2) a significant conflict of interest exists that will be managed
through a remedy agreed upon by both the affected individual
(investigator, family member, etc.) and the IRB;
3) a significant conflict of interest exists that cannot be adequately
managed and the research cannot be approved.
Possible remedies for conflicts of interest include:
1) reducing or eliminating the financial interest;
2) disclosing the financial interest to prospective subjects;
3) separating responsibilities for financial decisions and research
decisions;
4) providing additional oversight or monitoring of the research by
the IRB, an independent data and safety monitoring committee,
or similar monitoring body;
5) having an individual who does not have a potential or actual
conflict involved in the consent process;
6) modifying the roles of certain research staff;
7) changing the location for certain research actitivities.
All IRB Members, Investigators, Study Personnel, and the Institution must
abide by "Conflict of Interest" policies (Appendix B, Appendix C1).
10
Subjects. For all sponsored studies, subjects will be informed in the
consent document regarding who is sponsoring the study, who will
receive study funds, and how these funds will be used. For studies in
which the IRB has identified a significant conflict of interest, the subject
will be informed of the COI and how it will be managed.
11. Confidentiality:
All information reviewed by IRB members or discussed in committee will be
kept strictly confidential.
E. IRB Members Shall Include:
Regular Members:
one member of Hamot Medical Center Board of Trustees,
two corporators of Hamot Health Foundation Board of Trustees,
one representative of the community, who is neither a corporate nor a staff
member, is not otherwise affiliated with the institution, or not part of the
immediate family of a person that is affiliated with the institution,
at least three members of the medical staff,
at least one member each from the staff of the Medical Center Clergy, Nursing,
Pharmacy, and IRB Office,
at least one member whose primary concerns are in nonscientific areas; eg,
lawyers, ethicists, or members of the clergy, and
alternate members who represent particular and appropriate categories of
membership.
Consultants:
The IRB may, in its discretion and with the approval of the investigator, invite
individuals with competence in special areas, including vulnerable populations, to
assist in the review of complex issues which require expertise beyond or in addition to
that available from the IRB members. These individuals may not vote with the IRB.
F. Duties
Regular Members:
become familiar with the standards of professional conduct and practice, the
FDA, other regulatory agencies, Hamot Medical Center Research Policies and
Procedures, and IRB Policy and Procedures,
11
attend regular IRB meetings, and, if unable to attend, inform the Administrator at
least two days before the meeting,
maintain confidentiality of IRB activities and information,
carefully review and evaluate proposed research projects and consents, and
shall be entitled to vote once on each called vote at any meeting.
No proxy (written or phoned) votes are permitted.
Alternate Members:
are appointed to represent specific primary members at convened IRB meetings,
are identified on the IRB roster as to who they will represent,
will receive the same information and may participate the same as a primary
member; however, may vote only in the absence of the primary member. These
substitutions will be reflected in the IRB minutes.
Chairperson:
chairs all regular meetings or special sessions of the IRB (In the event of absence,
the chairperson designee shall chair the committee meeting. In the absence of a
chairperson designee, the Vice Chairperson shall perform this duty of the
Chairperson),
performs all functions of a regular member,
may temporarily suspend research that is not in compliance with IRB Policies and
Procedures,
represents the IRB in matters concerning HMC or the public when attendance of
the total membership is not required (may designate a substitute from the IRB),
participates in or designates others to participate in sessions designed to inform
and educate physicians, staff, students, and others concerning the aims and
functions of the IRB,
keeps abreast of the latest changes in federal, state, and local regulations
concerning ethical considerations involved in research using human subjects;
assists IRB members in similar efforts,
may authorize emergency changes in a protocol to avoid an immediate hazard to
subjects,
may provide expedited review and determines whether research is exempt from
IRB review.
12
Chairperson Designee:
In the absence of the Chairperson, the Chairperson Designee shall perform the
duties of the Chairperson as appropriate in accordance with HHS and FDA
regulations. The Chairperson Designee shall perform such other duties as are
assigned by the Chairperson.
Vice Chairperson:
In the absence of the Chairperson designee, the Vice Chairperson shall perform
the duties of the Chairperson as appropriate in accordance with HHS and FDA
regulations. The Vice Chairperson shall perform such other duties as are assigned
by the Chairperson.
Administrator:
develops, implements, and monitors educational activities concerning protection
of human subjects and IRB policies and procedures for investigators, study staff,
and IRB members,
facilitates completion of discipline specific peer review and administrative
approval,
orients new Chairperson or members in IRB procedure,
distributes IRB guidelines for application to physicians, staff, students, and
others, and provides guidance in the development of protocols,
screens all submission for conformity with the required format,
advises investigators of any additions or modifications that are necessary before
sending a submission for review,
arranges for bi-monthly meetings, prepares agenda,
records formal minutes,
reports the outcome of IRB reviews to investigators,
provides for periodic reviews of all on-going projects and informs the IRB of all
adverse events or unanticipated risks reported by investigators,
maintains records concerning all protocols and other IRB activities and
information,
participates in on-site reviews of IRB procedures and records by federal
inspectors,
maintains a Federal Wide Assurance with the Department of Health and Human
Services,
13
maintains the IRB Policy and Procedure manual in accordance with regulations
and guidelines from FDA, OHRP, and HHS,
provides assurances to federal agencies of approval of protocols that are supported
by federal funds,
acts as liaison between federal agencies and investigators regarding human
subjects issues,
may provide expedited reviews,
determines whether research is exempt from IRB review.
G. Meetings
Except where they conflict with the provisions of the Institutional Bylaws or policies
and procedures adopted by the Board of Trustees, the current edition of Roberts Rule
of Order, Revised shall govern all meetings of the IRB.
1. The IRB shall meet the first Tuesday of even numbered months at 5:00 pm in
the Board Room, first floor, Hamot Medical Center or at such time and place
as designated by the IRB Chairperson.
Note: If a quorum is not reached, the meeting will be scheduled the
following week or the earliest possible date that a quorum can be reached.
This is not to exceed one month.
Members shall be given written notice of each meeting of the IRB, setting
forth the time and place of the meeting, the matters of business to be
transacted, as well as the agenda and study material to be reviewed. Such
notice shall be sent by the Administrator and delivered to each member either
personally or by mail or electronic medium to his/her residence or place of
business as listed in the IRB records not less than seven days before such
meeting in the case of regular meetings and not less than 24 hours before such
meeting in the case of special meetings.
2. Action:
The IRB shall follow written procedures for conducting any review of
clinical investigations and human subject research. Such review shall
occur before the IRB reports its findings and actions to the investigator,
the institution, and where appropriate, the sponsor.
14
The IRB may re-consider its actions with or without submission of
additional information.
The IRB will review, discuss, and act on all protocols on the agenda.
3. Minutes:
Minutes reflecting the substance of all discussions shall be recorded for
every IRB meeting. Minutes are distributed to IRB members at least
one week before the next scheduled meeting, at which time the
Committee votes to accept the minutes as presented, or to require and
approve modifications and thereby accept the corrected minutes. The
final minutes are forwarded to Hamot Health Foundation Board of
Trustees for approval and to the Hamot Medical Center Board of
Directors for information only.
4. Order of Business:
The order of business at IRB meetings shall be as follows:
a. Call to order
b. Approval of previous minutes
c. New reviews
d. Continuing, Final, Expedited, Exempt and Emergency Reviews
e. Old business
f. New business
g. Education
h. Close meeting
5. Quorum
All significant business such as approval, disapproval, review, suspension,
or termination of a clinical investigation or human subject research shall be
conducted by the presence of a quorum that comprises a majority of
members participating in the meeting. This quorum must include one
licensed physician, one scientist, and one nonscientist.
An IRB member with a conflict of interest will not be counted toward
quorum as they must recuse themselves from the vote.
15
If an IRB member is functioning as the Principal Investigator, Co-
investigator, or Study Coordinator for a specific study, he/she is required to
leave the room for discussion and voting during initial protocol review.
This member no longer counts toward the quorum and this will be
documented in the minutes;
If an IRB member is functioning as the Principal Investigator, Co-
investigator, or Study Coordinator for a specific study, he/she will not be
required to leave the room for discussion and voting during continuing,
final, and amendment reviews unless:
1. he/she believes it would be appropriate;
2. another committee member requests it in advance by
contacting the IRB Chairperson;
3. a committee member requests it at the relevant IRB meeting; or
4. the IRB Chairperson believes it would be appropriate.
If this IRB member remains in the room for discussion and voting, he/she
will count towards the quorum, however, must abstain from voting on the
protocol.
When the IRB reviews research involving a vulnerable category of subjects
(ie, prisoners), one or more members who are primarily concerned with the
welfare of such subjects must be present.
H. Changes to Policies and Procedures
The policies and procedures of the IRB will be reviewed every two years by the IRB
Administrator or an ad hoc committee.
All changes to the IRB Policy and Procedure Manual must be adopted by a majority
of the IRB and approved by the Board of Trustees.
I. Records
Documentation
The IRB shall prepare and maintain adequate documentation of its activities
regarding each clinical investigation, including the following:
16
1. A list of IRB members identified by name; earned degrees; representative
capacity; indications of experience such as board certifications licenses, etc.,
sufficient to describe each member's chief anticipated contributions to IRB
deliberations; and any employment or other relationship between each member
and the institution; for example: full-time employee, part-time employee, a
member of governing panel or board, stockholder, paid or unpaid consultant
(Appendix H).
2. copies of written IRB procedures,
3. minutes of IRB meetings, including:
a) members present, as well as consultants, guests, and others,
b) a written summary of the discussion of any substantive issues and their
resolutions,
c) adverse reaction reports,
d) recommendations and actions, including a record of the number of
members abstaining or voting in favor or against the decision, etc.
4. a sign-in sheet for each IRB meeting with signatures of members and a listing
of guests,
5. records of information (including protocol and consent) submitted to the IRB
by an investigator and/or the sponsor,
6. copies of all correspondence between the IRB and the investigators (including
copies of all proposals reviewed, approved sample consent documents,
progress reports by investigators, and reports of adverse reactions to subjects),
7. dated reports of successive reviews as they are performed, and
8. when available, statements of significant new findings provided to subjects, as
well as
9. the basis for requiring changes in or disapproving research.
17
Retention
The IRB shall retain these records for at least three years after the completion of
the research and shall be accessible for inspection and copying by authorized
representatives of the FDA.
All IRB correspondence and meeting minutes shall be retained indefinitely. Study
files shall be reviewed annually. All terminated studies shall be placed in storage
for 15 years and then discarded.
J. Authority of the IRB
The IRB has the authority and responsibility to act with sound ethical principles and
in accordance with applicable regulations on behalf of HMC to approve, disapprove,
and monitor all research involving human subjects conducted by HMC physicians,
staff, and students.
The IRB shall function in compliance with laws, rules, regulations, and standards of
governmental, regulatory, and private accrediting agencies having jurisdiction over
HMC, in accordance with policies and procedures of the IRB and the Hamot Medical
Center (as approved by the Board of Directors).
The IRB has the authority to:
approve or disapprove a protocol or to require modifications to a protocol
(including the consent form) as a condition for approval,
oversee the conduct of a study and require progress reports,
suspend or terminate a study, or impose restrictions or require modifications to
a study as a condition for continuation.
The IRB does not have the authority to grant retroactive approval once human
subjects have already been involved in research.
An investigator whose protocol has been disapproved, modified, restricted,
suspended, or terminated by the IRB may, pursuant to the appeal procedures set forth
in Chapter III, request the IRB to reconsider the protocol.
No HMC administrator, physician, or staff member can override Committee
decisions. However, the protocol may be subject to further appropriate review,
disapproval, suspension or termination by the Hamot Health Foundation Board or
18
Board Committees. The HHF Board or Board Committee may not approve research
the IRB has disapproved.
K. Education of New IRB Chairperson and Members (Appendix H)
The Administrator and outgoing Chairperson will orient the new Chairperson and new
members to duties. The Administrator keeps them abreast of new developments and
provides articles and information for continuing education.
To assist the newly appointed IRB chairperson or members in understanding and
performing their IRB responsibilities, an educational packet is distributed for review.
The educational packet consists of:
"The role of the Institutional Review Board in Research Involving Human
Subjects", John A. Bosso, PharmD
"Office for Protection from Research Risks, CPA Information Packet"
"The Regulation of Investigational Drugs", David A Kessler, MD, JD
"The Belmont Report"
"Protection of Human Subjects, 45 CFR 46"
21CFR 50 & 56
L. Education of Investigators and Coordinators
In compliance with the Department of Health and Human Services requirements to
improve research integrity and prevent misconduct in research, the IRB shall be
responsible for the education and training of investigators and other research
personnel (Appendix H).
M. Resources of the IRB
Five file cabinets to maintain active and recently discontinued files, operational
files, correspondence, meeting packets minutes and other pertinent information.
A computer with printer
A copy machine
A facsimile machine
N. IRB Administrative Fee
The IRB will charge a standard administrative fee of $2,000 for review of research
protocols that are compensated. This administrative fee will apply to all compensated
19
studies, inclusive of studies with “no budget”, but with a set reimbursement of at least
$2,000/patient. This IRB fee will be waived for noncompensated studies, student
projects, and other special studies on a case-by-case basis at the discretion of the
Chairperson. Checks will be made payable to Hamot Medical Center and remitted to
the IRB Office. The one-time administrative charge will cover all IRB activities
including:
IRB application preparation and/or review,
Consent document preparation and/or review,
Initial review of study,
Review of all amendments, memos, revisions,
Review of serious adverse events, and
Continuing and final review of study.
20
CHAPTER II
SUSPENSION AND TERMINATION
OF A CLINICAL INVESTIGATION
The IRB has the authority to suspend or terminate approval of research that is not being
conducted in compliance with IRB/federal requirements or that has been associated with
unexpected serious harm to subjects. Any suspension or termination must be promptly
reported to the investigator, appropriate institutional officials, and federal regulatory
authorities (FDA or DHHS). Please note: humanitarian use device projects are also subject to
the policy set forth in this chapter.
A. Non-compliance: When questions arise concerning possible noncompliance
with IRB Policies and Procedures and other applicable regulations, the
Chairperson and the IRB have the authority to investigate and take appropriate
action to ensure compliance is restored or that the research is
suspended/terminated.
1. Serious Non-Compliance
The following actions will be considered serious non-compliance in keeping with
guidance received from the Office of Human Research Protection.*:
a. implementing human subject research that requires IRB review before
obtaining IRB review and approval,
b. deviating significantly from the standard informed consent process,
c. implementing substantive changes to an IRB-approved protocol without
IRB review and approval (except when necessary to eliminate or reduce
risks to the subjects),
d. any other situation that the IRB deems serious non-compliance.
2. Continuing Non-compliance
The following actions will be considered continuing non-compliance in keeping with
guidance received from the Office of Human Research Protection:
a. making the same mistake repeatedly, particularly after the IRB has informed
the principal investigator of the problem(s),
* ARENA and PRIM&R conference, 10/28-10/31/04, San Diego, CA.
21
b. having multiple problems with non-compliance over a long period of time,
c. having non-compliance problems with multiple protocols,
d. any other situation that the IRB deems continuing non-compliance.
3. Inquiry Regarding Non-compliance
Questions or concerns regarding noncompliance with IRB/federal requirements
should be directed to the IRB Chairperson or Administrator, who will report these
concerns to the IRB.
a. The IRB Chairperson may choose to confer with the investigator regarding
the potential non-compliance.
b. The Chairperson has discretion to temporarily suspend research under any of
the following circumstances:
1) substantial evidence of noncompliance,
2) reasonable suspicion of noncompliance, which may be associated
with more than minimal risk to human subjects,
3) information suggesting that the research involves substantially greater
risk than was anticipated at the time of initial IRB approval.
c. When research is temporarily suspended, the Chairperson will notify promptly
and in writing the following individuals of the suspension and reasons for it:
1) the investigator(s) (communication will include a copy of this chapter
of the HMC IRB Policy and Procedure),
2) the members of the IRB,
3) the IRB Administrator, who places the matter on the next IRB meeting
agenda,
4) the subjects, when appropriate. Subject notification will occur within
10 business days of notification of the investigator, sooner if significant
risk is involved. Some examples of when notifying subjects should be
considered include detection of a substantial increase in research risks,
an alteration in how the research will be implemented, a requirement
for increased monitoring due to potential side effects, etc.
22
d. The investigator may request that previously enrolled subjects continue to
receive treatment, evaluations, and tests in the study that has been suspended.
This request must be made in writing by the investigator within three business
days of receiving the letter of suspension from the IRB Chairperson. The
rationale for the request must be provided, along with the number of subjects
affected. The Chairperson will consider the ramifications of allowing subjects
to continue with study procedures/treatment versus discontinuing them from
participation. The Chairperson may need additional information from the
investigator to render a decision. The risks to subjects will be the primary
consideration. The Chairperson will also keep in mind the impact that missing
data points will have on the scientific validity of the research.
e. The Chairperson and Administrator will meet with the principal investigator
and study coordinator (if applicable) to assess the scope of the potential
noncompliance. Study records, consent forms, and other documents will be
requested for review.
f. The Chairperson may appoint an Ad Hoc committee to investigate potential
non-compliance. The Ad Hoc committee will consist of the Administrator, at
least one IRB member who is a physician, and at least one IRB member who is
a nonscientist. The Chairperson will serve on this committee at his/her
discretion.
1) The Ad Hoc committee will review the documents related to the
potential non-compliance and may meet with the principal investigator,
study coordinator, and other members of the study team to discuss the
potential non-compliance. If available, the Ad Hoc committee will
review the study team’s corrective action plan.
2) At the next IRB meeting, the Ad Hoc committee will report the results
of their inquiry and recommendations regarding research disposition to
the full IRB. At the Chairperson’s discretion, the investigator,
coordinator, etc. may be asked to attend the meeting. g. The IRB may confirm or rescind the original suspension, convert the
suspension to a termination, or take any other action deemed necessary that
is consistent with its authority and obligations. IRB actions may include,
but not be limited to:
1) requiring the investigator inform subjects of the noncompliance
and solicit their permission to publish the data,
23
2) requiring that the investigator and/or his study staff obtain
additional education,
3) performing random audits of the investigator’s study documents,
4) requiring that the investigator be mentored by another
investigator,
5) imposing restrictions as a condition of continuation of the
research,
6) allowing the principal investigator to continue providing care for
currently enrolled subjects with increased monitoring by the
IRB,
7) allowing a co-investigator to continue providing care for
currently enrolled subjects with increased monitoring by the
IRB,
8) asking the sponsor to make alternative arrangements at
another site to continue providing care for currently enrolled
subjects,
9) requiring the subjects terminate participation in the project and
obtain alternative medical care,
10) prohibiting the investigator from conducting human subjects
research at the Institution for a period of time.
h. Within seven (7) business days of their decision, the IRB will provide written
notice using the required format (Section 4, this chapter) to:
1) the investigator (communication will include a copy of the HMC IRB
Policy and Procedure manual Chapter III, Appeal Procedure),
2) the sponsor (if applicable),
3) the Departmental Chairperson, and
4) OHRP and/or FDA (FDA-regulated research) if the IRB is suspending
or terminating the project.
i. Suspension or termination of an investigation or research by the IRB may not
be overruled by the Board. Investigators may appeal the IRB ruling in writing
or verbally (See Appeal, Chapter III).
j. Provisions will be made regarding any subjects currently participating in the
research. Such provisions shall take into account:
1) the risks to the subject from withdrawal of the test article or
from continued administration by another physician,
24
2) the need for further medical supervision,
3) the availability of qualified medical personnel, and
4) the rights of the subject, including the right to participate in the
decision for future care.
k. Subjects, as appropriate, will be informed in writing regarding the inquiry, the
outcome, and any changes to the research. This notification will occur within
10 business days of notifying the investigator, sooner if significant risk is
involved.
l. If evidence of potential misconduct exists, the IRB will document the matter
and submit to the Chairperson of the Institutional Review Board for Potential
Misconduct and Conflict of Interest (the Senior Vice President of Medical
Affairs), who will follow the applicable administrative policies (Appendix
C1). The Administrator or appointed IRB Representative may consult with
FDA representatives regarding the circumstances of the potential misconduct
and report the information to the IRB.
4. Reporting Non-compliance
a. Within seven (7) business days, the IRB will submit a report concerning serious
or continuing noncompliance with IRB/federal regulation and/or suspension or
termination of the study, to the HMC departmental chair(s), the Senior Vice-
President for Medical Affairs, Office of Human Research Protections and/or
the Food and Drug Administration (FDA-regulated research), and other
agencies (as appropriate). This report should include the:
1) name of the institution where the research was conducted,
2) name of the principal investigator,
3) name of the research project and/or grant proposal in which
the non-compliance occurred,
4) number of the research project,
5) detailed description of the non-compliance (serious/continuing
noncompliance) ,
6) reasons supporting the decision to suspend/terminate the
research (suspension/termination of study) ,
7) corrective action plan,
25
8) actions the institution is taking or plans to take to address the
non-compliance or suspension/termination (e.g., education, random
audits, increased monitoring, etc.).
b. The report for the Office of Human Research Protection (Department of
Health and Human Services) will be forwarded to:
Director, Division Compliance Oversight
1101 Wootton Pkwy, Suite 200
Rockville, MD 20852
Fax – 304-402-0527
Ph – 866-447-4777 or 301-496-7005
For FDA Drug Products:
Ms. Dana Walters
Division of Scientific Investigations (HFD-45)
Office of Compliance
Center for Drug Evaluation and Research
White Oak Campus
10903 New Hampshire Ave.
BLDG 51, Rm. 5341
Silver Spring, MD 20993
Phone: (301) 796-3150
Fax: (301) 847-8748
For FDA Biologic Products:
Ms. Patricia Holobaugh
Bioresearch Monitoring Branch (HFM-664)
Division of Inspections and Surveillance
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research/FDA
1401 Rockville Pike, Room 400S
Rockville, MD 20852-1448
Phone: (301) 827-6347
Fax: (301) 827-6748
26
For FDA Medical Devices:
Ms. Sheila Brown
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire
WO66 RM 1651
Silver Spring, MD 20993
Phone (301) 796-6563
Fax: (301) 847-8120
B. Unexpected Serious Harm
Occasionally, an investigation may result in unexpected serious harm to participants.
These events may involve previously unknown side effects, an increase in the severity of
known side effects, an increase in the frequency of known side effects, etc. When
unexpected serious harm occurs, it should be reported to the IRB by the investigator (See
Chapter VII).
1. The IRB Chairperson may choose to confer with the investigator regarding
the unexpected serious harm. The IRB Chair will notify the IRB
Administrator who will place the matter on the next IRB meeting agenda.
2. If the Chairperson believes the unexpected serious harm is likely related to
the study, the Chair will provide an initial report to OHRP/FDA within a
few days of this determination.
3. The Chairperson has the discretion to temporarily suspend the research if
the data suggests that the research involves substantially greater risk than
was anticipated at the time of initial IRB approval.
4. When research is temporarily suspended, the Chairperson will notify promptly
and in writing the following individuals of the suspension and reasons for it:
a. the investigator(s) (communication will include a copy of this chapter
of the HMC IRB Policy and Procedure),
b. the members of the IRB,
c. the IRB Administrator, who places the matter on the next IRB meeting
agenda.
27
5. The Chairperson may require the investigator contact subjects regarding the
unexpected serious harm. Subject notification will occur within 10 business
days of notification of the investigator, sooner if significant risk is involved.
The investigator will be required to explain the nature of the harm, how the
harm impacts research participation, the risks of continued participation versus
withdrawal from the research, and that subjects may withdraw without penalty.
6. The IRB will review the data submitted by the investigator related to the
unexpected serious harm.
7. The IRB may confirm or rescind the original suspension, convert the
suspension to a termination, or take any other action deemed necessary that
is consistent with its authority and obligations. IRB actions may include, but
not be limited to:
a. providing written notification of the unexpected serious harm,
as soon as possible, but no more than 10 business days after
the IRB decision.
b. requiring additional monitoring or testing,
c. requiring additional provisions be made for subjects, as
appropriate. Such provisions shall take into account:
1) the risks from withdrawal of the test article or
from its continued administration,
2) the need for further medical supervision,
3) the availability of qualified medical
personnel,
4) the rights of the subject, including the
right to participate in the decision for future care,
5) the need to terminate participation and obtain
alternative medical care.
8. Within seven (7) business days of their decision, the IRB will provide written
notice to:
a. the investigator (communication will include a copy of the HMC IRB
Policy and Procedure manual Chapter III, Appeal Procedure),
b. the sponsor (if applicable),
c. the Departmental Chairperson, and
d. OHRP and/or FDA (FDA-regulated research).
28
9. The IRB notice should include the:
a. name of the institution where the research was conducted,
b. name of the principal investigator,
c. name of the research project and/or grant proposal,
d. number of the research project,
e. description of the unexpected serious harm,
f. corrective action plan,
g. reasons supporting the decision to suspend/terminate the
research,
h. actions the institution is taking or plans to take to address the
unexpected serious harm (e.g., revise protocol, suspend enrollment,
revise informed consent, inform subjects, increase monitoring of
subjects).
10. The report for the:
Office of Human Research Protection:
Director, Division Compliance Oversight
1101 Wootton Pkwy, Suite 200
Rockville, MD 20852
Fax – 304-402-0527
Ph – 866-447-4777 or 301-496-7005
For FDA Drug Products:
Ms. Dana Walters
Division of Scientific Investigations (HFD-45)
Office of Compliance
Center for Drug Evaluation and Research
White Oak Campus
10903 New Hampshire Ave.
BLDG 51, Rm. 5341
Silver Spring, MD 20993
Phone: (301) 796-3150
Fax: (301) 847-8748
29
30
For FDA Biologic Products:
Ms. Patricia Holobaugh
Bioresearch Monitoring Branch (HFM-664)
Division of Inspections and Surveillance
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research/FDA
1401 Rockville Pike, Room 400S
Rockville, MD 20852-1448
Phone: (301) 827-6347
Fax: (301) 827-6748
For FDA Medical Devices:
Ms. Sheila Brown
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire
WO66 RM 1651
Silver Spring, MD 20993
Phone (301) 796-6563
Fax: (301) 847-8120
11. Suspension or termination of an investigation or research by the IRB may not
be overruled by the Board. Investigators may appeal the IRB ruling in writing
or verbally (See Appeal, Chapter III).
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CHAPTER III
APPEAL PROCEDURE
If an investigator disagrees with an IRB decision or action, he or she may request
reconsideration by appearing before the IRB. This request must be made to the Chairperson
or IRB Administrator, in writing, within seven days of the date the investigator received
notification from the IRB.
Note: The entire appeal process must be completed within 120 calendar days of the date the
investigator received the notification from the IRB which he/she disputes.
A. The decision of the IRB becomes final under any of the following circumstances:
1. the investigator chooses not to appeal,
2. the investigator fails to notify the Chairperson or Administrator of the
decision to appeal within seven calendar days of receiving notification from
the IRB,
3. the investigator fails to appear before the IRB at its next regularly scheduled
meeting,
4. the investigator fails to make study documents available to the Institutional
Committee for Review of Potential Misconduct or Conflict of Interest within
seven calendar days of being requested to do so, and/or
B. The IRB will notify all appropriate parties of the Appeal.
C. The investigator must attend the next regularly scheduled IRB meeting to request
reconsideration of the decision. She/he will summarize the disputed request, as well as
supply information that supports his/her assertions. The IRB may affirm, modify or
reverse its original decision. If needed, the IRB may convene an Ad Hoc panel to
consider the new information and report back to the committee at the next regularly
scheduled meeting. The Administrator will notify the investigator of the Committee’s
decision.
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CHAPTER IV
QUORUM, EXPEDITED, AND EXEMPT REVIEW
All research falls into one of three categories; Quorum, Expedited, or Exempted Review
(Appendix G).
A. Quorum Review
"Quorum review" is the review of a protocol by a quorum of IRB members at the bi-
monthly IRB meeting. Quorum (full) review is necessary for research involving risk
of physical or psychological harm greater than that encountered in daily life or during
routine examinations or tests.
Procedure:
1. The Administrator gives the investigator the protocol application for
completion (Appendix D). The protocol must be submitted to the IRB
Administrator at least 30 days before the next meeting. Note: Studies must
receive peer review and administrative approval prior to review by the IRB as
specified in the policy, “Research Approval, Registration, Grants, Awards,
and Standards” (Appendix C). "The Guide to Protocol Development" assists
investigators in developing an original project (Appendix D). Documentation
of research approval must be obtained (Appendix D).
The IRB shall approve proposed clinical investigations or research involving
human subjects only after receiving and reviewing:
a. the complete, most current, written investigational or research protocol,
b. when applicable, the reports of pertinent prior animal and human studies
conducted with the test article,
c. the materials to be used for obtaining consent from the subjects,
d. the IRB Request for Approval of a Clinical Investigation Form,
e. any materials or information to be used for subject recruitment or for
advertisement.
33
2. The IRB Administrator reviews the submission and collaborates with the
investigator or coordinator regarding any modification. The Administrator
ensures that peer review and administrative approval is complete or in
progress.
3. The Administrator assigns an IRB number to the protocol. This number
consists of the review date and the number of the order in which the
submission is received. For example, the second study submitted for the June
1997 meeting is numbered 97-06-02.
4. The IRB Administrator forwards the proposal to the IRB Physician Reviewer
two weeks before the meeting. The Physician Reviewer is an IRB member
with appropriate medical or scientific background to perform an in-depth
review of the investigator's brochure, investigational protocol, and consent
form.
5. The Administrator distributes the "Request for Approval of Clinical
Investigation" form, the proposed consent document, and recruitment
materials, to primary and alternate IRB members one week before the
scheduled meeting. (A copy of the complete submission is available to all IRB
members upon request from the Administrator.)
6. The investigator or co-investigator must attend the IRB meeting to present the
study to the members. (When a resident or student presents to the IRB, he/she
must be accompanied by a faculty member who is an investigator for the
study.)
7. After presentation, the committee discusses the proposal with the investigator
and assesses risk (Appendix G).
8. The investigator is asked to leave the room, deliberation is conducted, and a
vote taken.
9. To approve research the IRB shall determine that all of the following
requirements are satisfied (21CFR 56.111 and 45 CFR 46.111):
a. risks to subjects are minimized,
b. risks to subjects are reasonable,
34
c. selection of subjects is equitable,
d. informed consent will be obtained,
e. informed consent will be appropriately documented,
f. where appropriate, the research plan makes adequate provision for
monitoring the data collected to ensure the safety of subjects,
g. where appropriate, there are adequate provisions to protect the privacy
of subjects and to maintain the confidentiality of data,
h. additional safeguards have been included in the study to protect the
rights and welfare of vulnerable subjects.
10. The IRB may:
a. approve the protocol as submitted. However, the protocol may be
subject to further appropriate review, disapproval, suspension, or
termination by the Hamot Health Foundation Board or Board
Committees. (Note: The HHF Board or Board Committees may not
approve research the IRB has disapproved),
b. require modifications, conditions or amendments (changes should be
submitted to the IRB within ten calendar days),
c. request additional information (should be submitted to the IRB within
ten calendar days),
d. disapprove the protocol. (If the protocol was not approved, or was
suspended, or terminated, see Chapter III - Appeal Procedures.)
Note: The decision of the IRB regarding a proposal shall not preclude a
different decision by the IRB of another institution considering the same
investigation or research.
11. Under extraordinary circumstances, the IRB has the option to meet via
telephone conference call provided that each participating IRB member: 1) has
received all pertinent material prior to the meeting and 2) can actively and
equally participate in the discussion of all protocols. Minutes of such meetings
must clearly document that these two conditions have been satisfied in addition
to the usual regulatory requirements. (46 FR 8967, January 27, 1981 and
OPRR-NIH-MSC 7507)
35
12. Investigator Bonus: If the investigator indicates that a bonus will be offered
related to patient recruitment on the Request for Approval of a Clinical
Investigation form, the IRB will consider the amount, timing, and
circumstances to assess whether the bonus might affect the investigator’s
judgement related to study implementation. If the IRB believes this
remuneration will have a significant impact, potential remedies include, but are
not limited to:
1. disallowing the bonus;
2. having a non-biased third party obtain consent;
3. providing increased IRB monitoring;
4. having a non-biased third party report and analyze data.
13. The IRB shall promptly inform the investigator in writing of the date the
application and the proposal will be reviewed. The investigator will also be
informed in writing by the IRB of the date that the investigation or human
research was:
a. approved (Appendix E),
b. approved pending modification (Appendix E) of the protocol,
research process, informed consent document, recruitment
materials, etc.
c. disapproved (stating the reasons). The investigator may choose
to appeal the IRB decision (see Chapter III-Appeal
Procedures). Some examples of circumstances that may lead to
disapproval include:
1) failing to comply with IRB procedures, federal
regulations, or requests for information,
2) submitting untrue statements to the IRB or omitting
required information,
3) providing reports of prior investigations that fail to
support the research is reasonably safe to initiate,
4) failing to possess the appropriate scientific training
and/or experience to qualify as a suitable expert in the
research field,
36
5) failing to determine that adequate laboratory and/or
medical support are available to ensure the study will be
conducted safely and properly,
6) failing to establish that research risks are reasonable
when compared with potential benefits,
7) failing to minimize the research risks (Appendix G),
8) failing to conduct the research in accordance with the
protocol submitted to the IRB.
14. The IRB shall in writing, inform the researcher of his/her responsibilities
(Chapter VI, Appendix E). The investigation or human research may not
begin until written notification of approval has been received from the IRB.
Note: The regulations do not prohibit direct sponsor-IRB contacts, although,
the sponsor-IRB interaction customarily occurs through the investigator who
conducts the clinical study. The clinical investigator provides the
communication link between the IRB and the sponsor. Such linkage is agreed
to by the sponsors and investigators when they sign forms FDA-1571 and
FDA-1572.
15. All approved studies are entered on the Study Summary Chart (Appendix H)
for tracking continuing, expedited, and final reviews.
The IRB may, at any time, suspend or terminate a previously approved clinical
investigation or human subject research if, for example, policies and
procedures are not adhered to or a subject is endangered. In addition, with the
suspension or termination of a clinical investigation, this same report shall be
made to the FDA and/or HHS, as appropriate.
16. A copy of the IRB minutes will be forwarded to the Hamot Health Foundation
Board for review.
B. Expedited Review
All research eligible for expedited review remains subject to the requirements of
informed consent except when a waiver or alteration is approved (Chapter VIII,
Informed Consent, D. Waiver).
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"Expedited review" is the review of a protocol by the IRB Chairperson and/or
Administrator and/or designee and applies to research of low or minimal risk. This
type of review may reduce the time required to obtain approval.
The expedited review procedure may not be used where identification of the subjects
and/or their responses would reasonably place them at risk of criminal or civil liability
or be damaging to the subjects’ financial standing, employability, insurability,
reputation, or be stigmatizing, unless reasonable and appropriate protections will be
implemented so that risks related to invasion of privacy and breach of confidentiality
are no greater than minimal. The expedited review procedure may not be used for
classified research involving human subjects.
1. Projects involving minimal risk may include:
a. Prospective collection of biological specimens for research purposes by
noninvasive means:
hair and nail clippings in a non-disfiguring manner,
deciduous teeth, or permanent teeth if an extraction is indicated,
excreta and external secretions including sweat and uncannulated
saliva,
placenta at delivery,
amniotic fluid at rupture of membrane before or during labor,
supra- and subgingival dental plaque and calculus in accordance with
accepted prophylactic techniques,
mucosal skin cells collected by buccal scraping or swab, skin swab, or
mouth washings, and
sputum collected after saline mist nebulization.
b. Collection of blood samples by finger stick, heal stick, ear stick, or
venipuncture as follows:
from healthy, nonpregnant adults who weigh at least 110 pounds. For
these subjects, the amounts drawn may not exceed 550 ml in an 8 week
period and collection may not occur more frequently than 2 times per
week; or
38
from other adults and children, considering the age, weight, and health
of the subjects, the collection procedure, the amount of blood to be
collected, and the frequency with which it will be collected. For these
subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml
per kg in an 8 week period and collection may not occur more
frequently than 2 times per week.
c. Research involving materials (data, documents, records, or
specimens) that have been collected or will be collected solely for
nonresearch purposes. If this is a retrospective review of de-
identified data, see Exempt Category #6.
d. Research of individual or group behaviors or characteristics of
individuals provided,
the investigator does not manipulate the subject's behavior,
the research will not involve stress to the subject,
the research will not involve deception of the subject (such
protocols would include studies of perception, cognitive game
theory, and text development).
e. Collection of data:
through noninvasive procedures (not involving general anesthesia or
sedation) routinely employed in clinical practice, excluding
procedures involving x-rays or microwaves. Where medical devices
are employed, they must be cleared/approved for marketing.
(Studies intended to evaluate the safety and effectiveness of the
medical device are not generally eligible for expedited review,
including studies of cleared medical devices for new indications.)
Examples:
1) physical sensors that are applied either to the surface of the
body or at a distance and do not involve input of significant
amounts of energy into the subject or an invasion of the
subject’s privacy;
2) weighing or testing sensory acuity;
3) magnetic resonance imaging;
39
4) electrocardiography, electroencephalography, thermography,
detection of naturally occurring radioactivity,
electroretinography, ultrasound, diagnostic infrared imaging,
doppler blood flow, and echocardiography;
5) moderate exercise, muscular strength testing, body
composition assessment, and flexibility testing where
appropriate, given the age, weight, and health of the
individual.
from voice, video, digital, or image recordings made for research
purposes.
f. Clinical studies of drugs and medical devices when:
an investigational new drug application (21 CFR Part 312) is not
required,
Note: Research on marketed drugs that significantly increases the
risk or decreases the acceptability of the risks associated with the
use of the product is not eligible for expedited review.
an investigational device exemption application (21 CFR Part 812)
is not required, or the medical device is cleared/approved for
marketing and the medical device is being used in accordance with
its cleared/approval labeling.
2. Expedited review can be used for continuing review of research, not conducted
under an investigational new drug application or investigational device
exemption where categories 1 through 5 do not apply, but the IRB has
determined and documented at a convened meeting that the research involves
no greater than minimal risk and no additional risks have been identified.
3. Expedited review also applies to previously (within 1 year) approved projects
that require minor changes. A minor change is one which, in the judgment of
the IRB reviewer, makes no substantial alteration in (1) the level of risks to
subjects; (2) the research design or methodology; (3) the number of subjects
enrolled in the research; (4) the qualifications of the research team; (5) the
facilities available to support safe conduct of the research; or (6) any other
40
factor which would warrant review of the proposed changes by the convened
IRB. Examples of minor changes in approved projects may include:
a. addition/deletion of subinvestigators,
b. asking patients to complete quality of life surveys, or
c. changing the duration of the project.
4. Expedited review procedures can be used for continuing review of previously
approved research activities where:
a. the protocol is permanently closed to the enrollment of new subjects,
all subjects have completed all protocol-related interventions, and the
protocol remains active only for long-term follow-up of subjects;
b. where no subjects have been enrolled and no additional risks have been
identified; or
c. where the remaining research activities are limited to data analysis.
5. Procedure:
Research involving minimal risk will be given expedited review by the IRB
Chairperson and/or the Administrator, as appropriate.
The Chairperson, Chairperson Designee, or Administrator also provides
expedited review for minor changes to an approved protocol. Changes must be
submitted to the IRB within ten calendar days of receipt by the investigator.
The Administrator coordinates and facilitates the expedited review procedure.
a. For new projects, the protocol, consent document, recruitment material,
and Request for Approval of a Clinical Investigation form must be
forwarded to the IRB Administrator. For ongoing projects, a summary of
the protocol/consent modifications, the rationale pertaining to the changes,
and the revised protocol/consent document, if applicable, must be
submitted to the IRB Administrator.
b. The Administrator screens all protocols for compliance with the required
format, inclusion of consent forms, and necessary signatures.
c. New projects will be reviewed by the IRB Chairperson and/or the
Administrator to determine if risk is minimal.
d. The Chairperson, Chairperson Designee, and/or Administrator will grant
expedited review and approval, as appropriate.
e. The Administrator will document the expedited review in a letter to the
researcher and for the record and will make a report to the IRB at the next
regular meeting (Appendix E).
41
f. If the IRB Chairperson and/or the Administrator do not approve the
research for expedited review, the project will be presented for full IRB
(quorum) review.
C. Exempt Research
"Exempt research" is research that does not require quorum or expedited review by
the IRB, although it requires an "Exemption of Approval". A project is exempt if all
the research activities present no risk to the patient. Although consent is typically not
required for exempt research, some universities may require documentation of
informed consent for student projects (Appendix D).
When evaluating research projects for exempt status, the first determination made by
the IRB Chairperson or Administrator is whether the study involves human subjects.
Per 45 CFR 46.102(f), human subjects are involved if:
a. an intervention or interaction occurs with a living person that would not
be occurring or would be occurring in some other fashion, but for the
research. (Intervention is defined as physical procedures and
manipulations of the subject or their environment. Interaction is defined
as communication or interpersonal contact between the investigator and
subject); or
b. identifiable private data/information is obtained in a form that can be
associated with an individual and their identity can be readily
ascertained (Typically, identifiable private data/information contains
one or more of the 18 HIPAA identifiers.)
If the research fails to meet one of the two criteria, human subjects are not involved
and the research can be found exempt from IRB review on that basis.
If the research meets the criteria for involving human subjects, it must fulfill one or
more of the following criteria to be considered exempt:
1. Research conducted in established or commonly accepted educational settings,
involving normal educational practices, such as:
a. research on regular and special education instructional categories, or
b. research on the effectiveness of, or the comparison among instructional
techniques, curricula or classroom management methods.
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2. Research involving only the use of educational tests (cognitive, diagnostic,
aptitude, achievement) if:
a. the data are recorded so that subjects cannot be identified in any way,
b. none of the investigator's own current students are subjects. (If
someone other than the investigator has contact with subjects, the study
can be exempt.)
3. Research involving only observation of public behavior. When subjects can be
identified in any way and any of the following conditions apply, the study must
undergo expedited or quorum review if:
a. the subject's responses or conduct (if they became public) may place the
subject at risk of criminal or civil liability or be damaging to the
subject's financial standing or employability,
b. the subject's responses deal with sensitive aspects of personal behavior
for example; illegal conduct, drug use, sexual behavior, use of alcohol,
c. the investigator participates in the activities being observed.
4. Research involving only surveys or interviews. If subjects can be identified in
any way or if subjects are children the study must undergo expedited or
quorum review.
5. Research involving only surveys or interviews of elected or appointed public
officials or candidates for public office is eligible for exemption. (Public
officials are defined as those individuals elected or appointed to local, state or
federal office.)
6. Research involving the collection or study of existing data (retrospective
study) including documents, records, pathological specimens, or diagnostic
specimens that are publicly available, or if the information is recorded by the
investigator in such a manner that human subjects cannot be identified in any
way. To qualify for exemption, the existing data must be de-identified as part
of health care operations by medical staff who are employed by the institution,
residents, medical interns, employees, or individuals who have signed a
Business Associate Agreement with the institution.
7. If the subjects are filmed or videotaped, the research can not qualify as exempt
and must undergo expedited or quorum review. However, some benign studies
(as determined by the chairperson) in which subjects are audiotaped may
qualify for exemption.
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8. Taste and food quality evaluations and consumer acceptance studies, if
wholesome foods without additives are consumed or if a food is consumed that
contains a food ingredient at or below the level and for a use found to be safe, or
agricultural, chemical, or environmental contaminant at or below the level found
to be safe, by the FDA or approved by the Environmental Protection Agency or
the Food Safety and Inspection Service of the U.S. Department of Agriculture.
Procedures:
1. The investigator must follow the research approval process (Appendix C),
complete a protocol development form (Appendix D), when applicable, and
consent (Appendix D), as appropriate, and then submit the protocol (Appendix
D) for approval and/or modification.
2. The approved protocol is then submitted to the IRB Administrator for review by
the Administrator and/or Chairperson to determine if the protocol meets the
criteria for exemption from Committee review.
3. The investigator is notified in writing, regarding the disposition of the project
(Appendix E).
(For students, written approval must be obtained from the investigator's school or
college IRB and the HMC IRB Administrator before beginning any research
activities involving human subjects.)
Note: The following schools and colleges located in Erie and the surrounding area
have their own IRBs: Penn State Erie - The Behrend College; Edinboro University
of Pennsylvania; Gannon University
4. When the project does not qualify for exemption, the Administrator or designee
will assist the investigator to prepare the protocol and consent for expedited or
quorum review.
5. When external funding is involved or institutional assurances are required, the
IRB Chairperson and/or Administrator will determine whether the research is
eligible for exemption, even if the investigator has obtained an exemption from
his/her college or university.
Note: Emergency (one-time) use of a test article can be exempt from IRB review,
provided such emergency is reported to the IRB within five working days (Ch. XI
Emergency (One-Time) Use of a Test Article).
44
CHAPTER V
MONITORING STUDIES
CONTINUING AND FINAL REVIEWS
All Quorum and Expedited Reviews will be subject to continuing and final reviews.
A. Continuing Review:
1. The IRB shall continue to review the approved project until it is concluded or
discontinued and no subjects/patients are being followed.
2. The IRB shall have authority to observe or have a third party observe the
consent process and the research (45 CFR 46.109 (e)).
3. Continuing review shall occur to assure that the investigation is being
conducted in compliance with the requirements, understandings, and
recommendations of the IRB, the FDA, and the HHS.
4. The frequency of continuing review will be determined at the time of initial
review and will occur at least once per year, will be recorded in the IRB
minutes, and the investigator will be notified in writing of the continuing
review date. When setting the interval for continuing review, the IRB will
consider:
The nature of any risks posed by the research project;
The degree of uncertainty regarding the risks involved;
The vulnerability of the subject population;
The experience of the investigators in conducting research;
The IRB’s previous history with the investigators;
The projected rate of enrollment;
Whether the research project involves novel interventions;
45
The associated animal studies when they indicate a significant risk for
humans;
The anticipated rate of severe adverse reactions.
5. The frequency of continuing review may be modified at any time as declared
necessary by the IRB.
6. The IRB may determine that certain projects need verification, from sources
other that the investigator, that no material changes have occurred since the
previous IRB review. When making this determination, the IRB will consider
whether:
a. the investigator has previously failed to comply with HHS regulations
or IRB Policy;
b. a concern exists that material changes may have occured without IRB
approval;
c. significant discrepancies were detected in information submitted to the
IRB.
The Chairperson will notify the investigator that verification of data is necessary.
Possible actions include, but are not limited to: 1) direct communication between a
representative of the IRB and the sponsor or their designee; 2) review of progress
reports from monitoring visits; 3) review of the Investigator Binder and at least five
consecutive signed consent forms (or all consent forms when less than five subjects
are enrolled); 4) review of individual case report forms and the corresponding medical
charts.
B. Final Review
A final review is accomplished to formally close a study by the IRB. An
investigation or research project may be closed for several reasons including:
1. has met the completion date of the original protocol,
2. is closed by the commercial sponsor, or
3. all follow-up is complete.
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C. Procedure for Continuing and Final Reviews
A Study Summary Chart identifying the status of all active projects is maintained
with the IRB files and updated bi-monthly to ensure timely review of ongoing
research protocols (Appendix H).
1. The Administrator reviews the Study Summary Chart for projects requiring
continuing or final review and forwards a letter and a Continuing/Final Review
Form to the investigator (copy to the coordinator) approximately six weeks
before the scheduled review (Appendix D, E).
2. The investigator must complete the Continuing/Final Review Form and
submit, with a copy of the currently used consent form, to the Administrator
three weeks in advance of the scheduled review. The Administrator checks
each form for completeness, resolves any questions, and places the study on
the meeting agenda.
3. When the Continuing Review Form has not been received by the Administrator
three weeks before the meeting, one phone call will be made to the
investigator/coordinator and one certified letter will be sent to the investigator
as a reminder to complete and submit the Continuing Review Form. If no
response is submitted before the scheduled IRB meeting, approval will be
terminated (See Chapter II for termination process – Please note: OHRP does
not require that a report be sent to them when a project is terminated for this
reason.)
4. A summary of all projects is forwarded to the committee for review on week
before the scheduled meeting. (The completed forms are available at the
meeting, as well as the study folder.) For continuing reviews the summary
includes:
The number of subjects accrued;
A summary of: 1) serious adverse events related/possibly related to the
study , 2) unanticipated problems that increase risk to subjects or others, 3)
withdrawal of subjects from the research, 3) complaints about the research
since the last IRB review;
A summary of any relevant recent literature, interim findings, and
amendments or modifications to the research since the last review;
47
Any other relevant information, especially information about risks
associated with the research; and
A copy of the current informed consent document and any newly proposed
consent document. The Administrator will review the document to verify
that the most accurate, up-to-date version is provided to the subject. If the
site is not using the appropriate version, the Administrator will report this
to the Committee and the Investigator. As part of the consent document
review, the IRB will consider whether any significant new information has
been adequately disclosed and whether risks and discomforts have been
appropriately described.
5. As with initial review, the following requirements must be satisfied:
a. risks to subjects are minimized and reasonable,
b. selection of subjects is equitable,
c. informed consent will be obtained,
d. informed consent will be appropriately documented,
e. where appropriate, the research plan makes adequate provision
for monitoring the data collected to ensure the safety of subjects,
f. where appropriate, there are adequate provisions to protect the
privacy of subjects and to maintain the confidentiality of data,
g. additional safeguards have been included in the study to protect
the rights and welfare of vulnerable subjects.
6. The IRB may:
a. approve the continuing review information as submitted.
b. require modifications, conditions or amendments to the protocol,
consent document, or research process to allow the study to
continue (changes should be submitted to the IRB within ten
working days),
c. request additional information (should be submitted to the IRB
within ten working days),
d. convert the continuing review to a final review and provide the
investigator with the rationale for doing so. The investigator can
appeal this decision. (see Chapter III - Appeal Procedures.)
6. A letter is forwarded to the investigator and copied to other pertinent parties
indicating continuing review approval or termination of the project (Appendix
E). The study summary chart is updated regarding continuing or final review.
For continuing studies, the next review date is listed.
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CHAPTER VI
STUDY PERSONNEL
Investigator
Investigators must have the appropriate scientific and medical background, as well as
expertise in the area in which the research will be conducted.
Investigators are responsible to:
1. submit to the IRB Administrator
a. a Request for Approval form (Appendix D), b. a Documentation of Research Approval form c. the protocol, d. the investigator's brochure, e. reports of any previous animal and/or human studies, f. materials to be used in obtaining the consent of human subjects, g. any advertisements for recruiting subjects, h. a curriculum vitae (CV), except when the investigator is on staff at Hamot
Medical Center, Regional Cancer Center, or Shriners’ Hospitals for Children. A CV will also be required if requested by one of the members of the IRB.
i. following approval; a periodic written progress report (continuing review), and
j. a final report.
Note: Failure to respond to IRB requests (eg, continuing or final reports) will
result in withdrawal of IRB approval.
2. successfully complete the IRB Basic Education Program
3. attend the IRB meeting to initially present the protocol or additional
information (When a resident or student presents to the IRB, he/she must be
accompanied by a faculty member who is an investigator for the study.),
4. await written IRB approval before involving human subjects in the study,
5. receive an "Exemption" letter before involving human subjects in any exempt
research project,
49
6. submit any changes to a protocol or consent form to the IRB within ten
calendar days of receipt (if applicable). Changes may include:
a. adding investigators, b. changing methods for conducting the trial, c. modifying consent forms, etc.
7. Receive written expedited or full approval before implementing changes,
8. comply promptly with accurate and adequate information to all IRB requests
concerning a protocol,
9. conduct the clinical investigation according to the protocol:
a. Protocol
1) Each clinical investigation shall have a written plan.
2) All changes or revisions to a protocol, and reasons therefore, shall be
documented by the investigator, dated, and maintained with the
protocol.
b. Amendments/changes
1) An investigator shall not implement a change in the protocol, if the
change or deviation may increase the risk to subjects or may adversely
affect the validity of the investigation or the rights of the human
subjects without the prior review and written approval of the sponsor
of the investigation and the IRB.
2) If changes to a protocol become necessary, investigators must obtain
IRB approval before instituting such changes.
3) The entire amended protocol and consent form must be submitted for
review and approval by the IRB.
a) Major changes are those that directly affect the level of risk to the
subjects. Major changes must undergo quorum review. Examples
include, but are not limited to:
the addition of new, vulnerable populations as subjects,
changes in strategies or interventions,
alterations in drug dosage or period of administration, or
changes in enrollment age that negatively affect risk or result in
recruitment of a vulnerable population.
b) Minor changes are those that do not affect the level of risk to
subjects. (See Chapter IV, B. Expedited Review)
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When a change is made to eliminate or reduce the risk to human subjects, it may be
implemented before review or approval by the sponsor and the IRB. The investigator
shall notify the sponsor and the IRB in writing within ten (10) working days after
implementation.
In drug and biologic studies, the investigator must notify the sponsor of proposed
changes in a protocol. For significant risk devices, except when the deviations are
necessary to protect the life or physical well-being of a subject in an emergency, FDA
must approve all changes or deviations from the investigational plan that may affect
the plan's scientific soundness or subject rights, safety, or welfare. Deviations that are
necessary to prevent harm should be reported to the IRB and to the sponsor, who
should report the deviations to FDA.
The procedure for submitting protocol changes to the IRB includes:
a. A detailed letter describing the nature of the requested changes, the
reasons for making each change, and any possible effect the changes may
have on subjects.
b. For changes involving a different principal investigator or a new co-
investigator, attach the new investigator's name, signature, and title.
Investigator qualifications (curriculum vitae) may be requested.
c. For changes to the consent form, submit a new consent form with
notations indicating any language on the new form that differs from that
previously approved by the Committee.
d. For modifications to any other attachment(s), submit the changes with
notations indicating any language that differs from that originally
approved.
10. notify the IRB promptly of:
a. serious adverse reactions (See Chapter VII)
b. unanticipated problems that result in increased risk
c. protocol deviations that result in increased risk
d. termination of human subject involvement, and
e. completion of the study (See Chapter V).
11. maintain records of all submissions to and all actions by the IRB regarding the
clinical investigation,
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12. retain all study records (case report forms, office files, appointment books,
regulatory documents, correspondence, etc.,) for:
a. drug and biologic studies
1) at least two years following the date on which the study drug is
approved by the FDA for marketing for the purposes that were the
subject of the investigation, or
2) at least five years following the date on which the results of the clinical
investigation for a research or marketing permit is requested for the
purposes that were the subject of the investigation,
b. device studies
1) for two years after the later of the following dates: the date on which
the investigation is terminated or completed or, the date that the
records are no longer required to support a premarket approval
application or a notice of completion of a product development
protocol.
Note: For device studies, the investigator must maintain a record of the
exposure of each subject to the investigational device, including the
date and time of each use, and any other therapy.
13. report significant new findings to subjects, particularly if it could affect their
willingness to participate,
14. transfer records to another person or group who will accept responsibility for
the records, e.g., the manufacturer, or another investigator in the event the
investigator retires, relocates, or for any other reason withdraws from the
responsibility of maintaining records for the period of time required. (Written
notice of such transfer must be submitted to the IRB and the sponsor.)
To comply with FDA record retention requirements, clinical investigators
should arrange to be kept informed by study sponsors of the status of the
application for their respective studies.
52
Note: The investigator may maintain all study records or, in those cases in which the subject
is a patient in a hospital or other facility, the records may be maintained as part of the patient
hospital or clinical record. If a hospital or clinic keeps the records, the investigator must
ensure that the records are retained at least for the length of time set forth by the regulations.
An investigator may retain records either in their original form or by means of microfilm,
microfiche, photocopies, or other accurate reproductions of the original records. If copies are
used, however, they must be legible and the investigator is required to assure that such
reproductions are true and accurate copies of the original. When reproduction techniques
(e.g., microfilming) are used, a reader and photocopying equipment should be readily
available. If written notes, erasure marks, or other changes are not apparent on the
reproduction, a notation of this fact should be clear on the reproduction of the record and the
original records should be retained for the time required.
Raw data, entered directly into a computer system, are considered to be the original or true
copy of the data whether it is printed out as a hard copy or stored as computer files. An
acceptable computerized data collection system would be one that: (1) allows data entry only
by authorized individuals; (2) controls the ability to delete or alter previously entered data
and provides an audit trail for such data changes (e.g., modification file); (3) protects the data
base from tampering; and (4) ensures data preservation. If records are retained in a computer
data system, suitable equipment should be readily available to produce a hard copy of the
data. Data should be retrievable in such a fashion that all information regarding each
individual in a study is attributable to that individual, i.e., case report equivalents must be
available.
FDA may audit any and all records that might support microfilm, microfiche, or other stored
data. These records must be maintained just as paper case report forms must be maintained.
Coordinator
Research Coordinators must meet the employment requirements of Hamot Medical Center
and successfully complete the IRB Basic Education program. In addition, the Research
Coordinator must complete one of the following:
the Comprehensive Clinical Research Coordinator Education Program from Barnett
International (FDA-regulated research). A comparable program may fulfill this
requirement pending IRB Chairperson review and approval;
Foundations of Clinical Research Self Study Program, The Center for Clinical
Research Practice, available through the IRB Administrator (FDA-regulated research);
Hamot Research Coordinator Education Program available through the IRB
Administrator (non-IND/IDE research).
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CHAPTER VII
ADVERSE EVENTS AND UNANTICIPATED PROBLEMS
INVOLVING RISKS TO SUBJECT/PATIENT OR OTHERS
A. Definitions
1. Adverse Event (AE)
Any unfavorable and unintended diagnosis, symptom, sign, syndrome, or
disease that occurs during the subject’s enrollment in a study if absent or less
severe at baseline.
2. Serious Adverse Event (SAE)
Any adverse experience that is considered related or possibly related to the
study and results in any of the following outcomes:
a. death
b. a life-threatening adverse experience (Any adverse drug experience that
places the subject, in the opinion of the investigator, at immediate risk
of death from the reaction as it occurred, i.e., it does not include a
reaction that, had it occurred in a more severe form, might have caused
death).
c. inpatient hospitalization or prolongation of existing hospitalization
d. a persistent disability/incapacity (A substantial disruption of a person’s
ability to conduct normal life functions.)
e congenital anomaly/birth defect
Additionally, important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse
experience when, based upon appropriate medical judgment, they may
jeopardize the patient or subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition.
54
Examples of such medical events include allergic bronchospasm requiring
intensive treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in hospitalization, or the development of
drug dependency or drug abuse.
3. Unanticipated Problem (UP)
Any incident, experience, event, or outcome that meets ALL of the
following criteria:
a. Unexpected (in terms of nature, severity, or frequency) given (a)
the research procedures that are described in the protocol-related
documents and (b) the characteristics of the population being
studied.
b. Related or possibly related to participation in the project
c. Suggests that the project places subjects/patients at greater risk
of harm.
B. Relatedness – defined as the best estimate of the PI at the time that the SAE or UP is
reported of the causal relationship between an intervention and the serious adverse
event/unanticipated problem.
1. Unrelated – event is clearly due to extraneous causes (e.g.,
underlying disease, the environment, etc.)
2. Possibly related - Must include at least 2 of the following:
a. A reasonable temporal relationship to the intervention;
b. Could not readily have been produced by the subject’s
clinical state;
c. Could not readily have been due to environmental or other
interventions;
d. Follows a known pattern of response to the intervention.
3. Related – Must include all 4 of the following:
a. A reasonable temporal relationship to the intervention;
b. Could not readily have been produced by the subject’s
clinical state or have been due to environmental or other
interventions;
c. Follows a known pattern of response to the intervention;
d. Disappears or decreases with reduction in dose or cessation
of intervention and recurs with re-exposure.
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C. Reporting
1. Investigators are responsible to:
a. record and report all AEs, SAEs, and UPs to the Sponsor/Manufacturer
per Sponsor/Manufacturer requirements (typically defined in research
protocol.)
b. record and report all SAEs, and UPs to the IRB as follows:
1) By telephone within 24 hours (or within 24 hours of knowledge of
the event) followed by a written report within five days after the
event using the appropriate IRB form (Serious Adverse Event or
Unanticipated Problem form [Appendix I]).
2) At continuing review
D. Actions taken by IRB
The IRB will evaluate all reports of Serious Adverse Events and Unanticipated
Problems at a convened meeting. Some of these reports will be on-site events and
others will be off-site events (ie., multicenter trial). The committee will consider
whether corrective actions or substantive changes need to be instituted in response to
these reports. Possible actions include:
Modification of inclusion/exclusion criteria;*
Implementation of additional procedures for monitoring subjects/patients;*
Suspension of enrollment of new subjects/patients;*
Suspension of research procedures in currently enrolled subjects;*
Modification of informed consent documents to include description of newly
recognized risks;*
Provision of new information regarding risks to previously enrolled
subjects/patients.*
* For clinical trials, this will often be addressed in a study amendment.
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CHAPTER VIII
PROTOCOL DEVIATIONS
Federal regulations require that IRBs develop written procedures that will ensure prompt
reporting by the study team of any changes in research activity. Protocol deviations represent
one such change in the IRB-approved research. Protocol deviations must be reported to the
IRB by the investigator or his/her designee. These reports are reviewed by the IRB to
determine whether the previously approved protocol, informed consent document,
risk/benefit ratio, and study procedures remain acceptable. The IRB also uses reports of
protocol deviations as a way of tracking adherence to the protocol and Good Clinical
Practice. If the investigator is not implementing the protocol as approved, the IRB may
choose to suspend or terminate that approval.
A. DEFINITIONS
1. Protocol Deviation – A failure to follow procedures specified in the approved
research submission.
2. Pre-approved Protocol Deviation – A prospective decision by the investigator,
sponsor, and IRB to allow a deviation from the approved research submission.
3. Minor Protocol Deviation – A deviation that has little or no impact on subject
Safety, the risk/benefit ratio, value of data collected, research design, or scientific
conclusions.
4. Major Protocol Deviation – A deviation that has harmed or posed a significant
risk to a subject, or has compromised the scientific integrity of the study.
B. PROCEDURES
1. Pre-approved Protocol Deviations
a) When the investigator wants to deviate from the approved research
submission (e.g., wishes to enroll a subject who does not meet the
approved inclusion/exclusion criteria; wants to schedule a follow-up
visit outside the study window because the patient is out of town; etc.)
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he/she must submit a written request to the IRB Administrator.
Included with this request should be written approval for the deviation
from the Sponsor. Depending on the nature of the deviation, approval
may be given through expedited review by the Chairperson,
Administrator or designee, as appropriate. Whenever a potential
concern exists regarding subject safety, the deviation will be presented
to the full IRB for review.
b) If the deviation is approved as submitted, the investigator will be
notified in writing.
c) If the requested deviation results in significant safety/study design
concerns, the investigator may be asked to provide additional
information to the committee or be asked to attend the next IRB
meeting to explain his/her request. The IRB decision regarding the
requested deviation will be conveyed to the investigator in writing.
d) If the requested deviation is considered a revision of research activity,
the IRB may require that the change be submitted as an amendment to
the protocol.
2. Minor Protocol Deviations
When minor protocol deviations occur, they may be reported at the time of continuing
review. These deviations do not affect the scientific soundness of the research plan or
the rights, safety, or welfare of the human subjects. Examples of minor deviations
include: 1) drawing blood samples close to, but not precisely, at the specified time
points; 2) a subject who cancels their follow-up visit and is unable to reschedule until
after the study window has closed; 3) inadvertently skipping questions on a quality of
life questionnaire in an investigational drug study.
3. Major Protocol Deviations
a) The principal investigator is responsible for reporting all Major
Protocol Deviations to the IRB as soon as possible, but no later than 5
working days after the investigator becomes aware of the event.
b) These deviations should be reported using the Protocol Deviation Form
(Appendix J).
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c) If the deviation resulted in a Serious Adverse Event, the Serious
Adverse Event Form must be completed, as well.
d) If IRB members ask for additional information regarding the deviation,
this will be communicated to the investigator by the Administrator and
a written response requested. At the Chairperson’s discretion, the PI
may be asked to attend the next IRB meeting to explain the reason for
the protocol deviation, how the subject was impacted, and how the
deviation will be prevented in the future.
e) The Protocol Deviation Form, Serious Adverse Event Form (if
applicable) and additional information (if requested) will be distributed
to the IRB members at the next regularly scheduled meeting.
f) The committee will consider the information submitted by the PI and
determine whether the response was adequate or whether additional
actions or follow-up is needed. Further actions may include, but are not
limited to:
1) revisions to the protocol, consent document, or corrective action
plan;
2) audit of the study by the IRB;
3) increased frequency of continuing review;
4) suspension or termination of the study.
g) The PI will be notified, in writing, of the IRB decision after the
protocol deviation is reviewed.
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CHAPTER IX
QUALITY IMPROVEMENT AUDIT
The Office of Human Research Protection has recommended that the IRB move toward a
system of interacting with investigators that is proactive and emphasizes prevention of harm.
To accomplish this, the Administrator will perform a Quality Improvement Audit of
Investigational Drug, Investigational Device, and Humanitarian Use Device Projects. This QI
audit is intended to evaluate and improve both institutional systems and individual research
projects with emphasis placed on the responsible conduct of research.
Because research involving investigational drugs/devices typically present the greatest risk of
harm to subjects, and humanitarian use device (HUD) projects can be particularly difficult to
implement, these projects are the main focus of the QI Audit. The audit will allow the IRB to
provide timely feedback/education to the investigators regarding implementation of
subject/patient protections. It will not only help investigators/staff identify areas that are or
could become non-compliant with regulatory standards, but will also provide methods to
meet best practices. The audit will allow the IRB to verify that Research/HUD projects are
being conducted in an appropriate fashion.
As new Research/HUD projects are instituted, the Principal Investigator (PI) and Study
Coordinator will be asked to notify the IRB Administrator when the first subject/patient is
enrolled in the project. Every effort will be made to schedule the Quality Improvement Audit
within one month of enrollment. The Administrator will review the Investigator (Regulatory)
Binder, Medical Chart, and Case Report Form (when possible) utilizing the Quality
Improvement Audit Form (Appendix K). The review may also include interview of study
personnel and observation of Research/HUD practices. The presence of the Principal
Investigator/Study Coordinator during the review is optional. If desired, a brief meeting can
be scheduled to discuss the results after the audit is complete. A written report of the Quality
Improvement Audit will be forwarded to the PI with copies to the Study Coordinator and IRB
Chairperson. The PI can provide a written response to the report, if desired, within 30 days of
report receipt. The response should include: 1) identification of any inaccuracies; 2) an
explanation of circumstances (extenuating or otherwise) that could account for certain
findings, and 3) acknowledgement of findings requiring correction. The PI’s comments will
be forwarded to the IRB Chairperson for review, attached to the QI Audit report, and placed
in the IRB file. The report may be forwarded to the IRB for review at the IRB Chairperson’s
discretion. This will typically occur if a significant deviation from standard practice has been
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identified, the deviation threatened the safety of participants, or the process that lead to the
deviation has been inadequately addressed. The IRB will take action, as appropriate.
If during the audit, the Administrator identifies noncompliance that may be serious or
continuing, the Administrator will:
immediately notify the PI or the PI designee
promptly notify the IRB Chairperson.
If the compliance is found to be serious/continuing, the Chairperson will follow pertinent
IRB procedure (Chapter II, Suspension and Termination of a Clinical Investigation).
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CHAPTER X
INFORMED CONSENT
When a clinical investigation places any human subject at risk, the investigator must first
obtain and document informed consent of the subject or the subject's legally authorized
representative. Pennsylvania law, P.S. 1301.811A, requires the physician investigator to
obtain informed consent when administering an experimental medication, using an
experimental device or using an approved medication or device in an experimental manner.
All investigators obtaining consent for subject enrollment must be approved by the IRB.
Under the Department of Health and Human Services (HHS) regulations, information
provided for the purposes of oral or written informed consent may not include any
exculpatory language through which the subject is made to waive, or appear to waive, any of
his/her legal rights, including release of the investigator, the sponsor, or the institution or its
agents from liability for negligence.
The consent document itself is a written summary of the information that should be provided
to the subject including any human subject who is a control (Appendix D). (Many clinical
investigators use the consent document as a guide for the verbal explanation of the study.
Reading grade level of the document should be a maximum of 8th grade.) The subject's
signature provides documentation of consent to participate, but this is only one part of the
consent process.
The entire informed consent process should:
1. give a subject adequate information concerning the study,
2. provide adequate opportunity for the subject to consider all options,
3. provide adequate opportunity for the investigator or designee to respond to the
subject's questions,
4. ensure to the best of the investigator's ability, that the subject has
comprehended this information,
5. obtain the subject's voluntary agreement and signature to participate, and
6. continue to provide information as the subject or situation requires.
To be effective, the process should provide ample opportunity for the investigator and the
subject to exchange information.
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The IRB should ensure that technical and scientific terms are adequately explained or that
common terms are substituted. The IRB should ensure that the informed consent document
properly translates complex scientific concepts into simple words that the typical subject can
read and comprehend. The IRB Administrator will perform a preliminary review of each
consent document to ensure federal requirements are met.
A. Elements
(Note: The first eight basic elements of informed consent are designated in 21
CFR 50.25. The remaining elements (9-12) are required by Hamot IRB.)
1. A statement that the study involves research, an explanation of the purpose of
the research, the expected duration of the subject's participation, the
approximate number of subjects who will participate in the study, a description
of the procedures to be followed, and identification of any procedures that are
experimental.
2. A description of any reasonably foreseeable risks or discomforts to the subject.
3. A description of any benefits to the subject or to others that may reasonably be
expected from the research.
4. A disclosure of appropriate alternative procedures or courses of treatment, if
any, that might be advantageous to the subject.
5. A statement describing the extent, if any, to which confidentiality of records
identifying the subject will be maintained, and the possibility that the Food and
Drug Administration (FDA) may inspect the records.
Note: State that research records may become part of a participant's hospital or
medical records. Explain that for all drug and device studies records will be
kept confidential to the extent permissible by law.
6. For research involving more than minimal risk, an explanation as to whether
any compensation will be paid to subjects, whether any medical treatment will
be available if injury occurs, and, if so, what the treatment consists of, or
where further information may be obtained.
7. An explanation of who to contact for answers to pertinent questions about the
research, the research subject's rights, and who to contact in the event of a
research-related injury to the subject. (Phone numbers should be included.)
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8. A statement that participation is voluntary, that the subject may refuse to
participate or discontinue participation at any time, and that the refusal or
discontinuation will involve no penalty or loss of benefits to which the subject
is otherwise entitled.
9. A statement that significant new findings that may develop during the course
of the research and may relate to the subject's willingness to continue
participation will be provided to the subject.
10. A statement that the subject's questions about the research have been
answered.
11. A statement that the subject will receive a copy of the consent form.
12. Lines for the following signatures and dates for each:
a. the subject or the subject's authorized representative,
b. the investigator, and
c. an impartial witness.
B. Additional Elements
When appropriate, one or more of the following elements of information shall also be
included in the consent form:
1. A statement that the particular treatment or procedure may involve risks to the
subject (or to the embryo or fetus, if the subject is or may become pregnant)
that are currently unforeseeable.
2. Anticipated circumstances under which the subject's participation may be
terminated by the investigator without regard to the subject's consent.
3. Financial Considerations:
a. Describe any monetary rewards or payments to the subject for
participating; include the payment schedule and an explanation of the
extent to which payment will be made if the subject withdraws or is
removed from the study prior to its completion.
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b. Explain any costs associated with participation. For studies involving
clinical treatment, this includes expenses associated with the study that
would not ordinarily be incurred with standard treatment for the
subject's condition.
c. For studies involving more than minimal risk, state whether or not costs for
medical treatment will be provided if injury occurs as a consequence of the
research.
d. For studies involving more than minimal risk, state whether or not any
money will be paid voluntarily as compensation for injury (eg, for lost
wages or for pain and suffering) that occurs as a consequence of the
research.
e. For all sponsored studies, state who is sponsoring the study, who will
receive study funds, and how these funds will be used. For studies in
which the IRB has identified a significant conflict of interest (COI),
inform the subject regarding the COI and how it will be managed.
4. The consequences of a subject's decision to withdraw from the research, and
procedures for orderly termination of participation by the subject.
5. A statement that informs participants if the research is being performed to
fulfill requirements for a doctoral dissertation, master's thesis, or classroom
assignment.
6. The approximate number of subjects involved in the study.
C. Documentation
A copy of the signed consent document must be placed on the patient's chart/medical
record after consent is obtained. A copy should be immediately given to the patient.
The original should be placed with the study records. The actual procedure for
obtaining legally effective, adequate, and appropriate informed consent will be fully
documented by using one of the following forms:
1. A written document including the "basic elements" of informed consent, as
well as the "additional elements" as appropriate, may be read to the subject
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or the subject’s legally authorized representative; however, both must be
given adequate opportunity to read and sign the written consent. A copy of
the consent document must be given to the subject at the time the consent
form is signed.
2. In rare instances, such as in studies of subjects in emergency situations, or with
impaired sight (e.g., blind or dyslexic), or illiterate subjects who are fully
capable of consenting, but are not capable of reading or signing a consent
form, the IRB may approve the use of a short form document with an oral
narrative.
The short-form consent document with the oral narrative must include:
a. a narrative that contains all the information and elements of the standard
consent form.
b. the signature of the impartial witness on the narrative and the short-form
consent document to verify that the oral and written information are the
same. A witness must be present when the narrative is read to the subject.
c. the signature of the authorized representative on the short-form consent
document stating the subject willingly agrees to participate in the research
described in the narrative.
d. the signature of the investigator on both the narrative and the short-form
consent document.
The investigator then gives the subject copies of both the narrative and the
short-form consent document. The investigator must submit a letter to the
sponsor and the IRB (addressed to the IRB) requesting this procedure and
explaining why it is appropriate, with a copy of the narrative that will be
read to the subjects and the short-form consent document.
3. Non-English Speaking Study Subjects
a. When the study subject population includes non-English speaking people,
or the clinical investigator or the IRB anticipates that the consent
interviews will be conducted in a language other than English, the IRB
should require that an accurately translated consent document be prepared.
The translated document and the original approved consent form should be
given to the subject.
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b. If a non-English speaking subject is unexpectedly encountered,
investigators will not have a written translation of the consent document
and must rely on oral translation. Investigators should carefully consider
the ethical/legal ramifications of enrolling subjects when a language
barrier exists. If the subject does not clearly understand the information
presented, the subject's consent will not truly be informed and may not be
legally effective. (If investigators enroll subjects without an IRB-approved
written translation, a "short form" written consent document in a language
the subject understands should be used to document that the elements of
informed consent were presented orally.)
4. A person who speaks and understands English, but does not read and write,
can be enrolled in a study by "making their mark" on the consent document.
Development of a short form or a narrative statement is not required, but an
impartial witness should be present to attest to the adequacy of the consent
process and to the subject's voluntary agreement. The signatures required by 21
CFR 50.27(b)(2) are necessary. These include:
a. the subject or the representative,
b. the impartial witness, and
c. the investigator or the person obtaining the informed consent.
C. Waiver
1. Informed consent may be waived in an emergency situation
(Emergency Use of a Test Article, A.4.).
2. The IRB may approve a consent procedure which does not include, or
which alters, some or all of the elements of informed consent, or waive
the requirements to obtain informed consent provided the IRB finds and
documents that:
a. the research involves no more than minimal risk to the subjects;
b. the waiver or alteration will not adversely affect the rights and
welfare of the subjects;
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c. the research could not practicably be carried out without the
waiver or alteration; and
d. whenever appropriate, the subjects will be provided with additional
pertinent information after participation.
Note: Written informed consent may be required at the discretion of
the IRB chairperson, even if the study poses "no" or "minimal" risk.
3. The reason for waiving consent (as appropriate) must be documented on
the approval letter and in the minutes of the IRB meeting in which the
waiver is reviewed or approved. Protocol-specific information
justifying each IRB finding must be included.
